Development of distinct intestinal epithelial cell types is central to normal gut function, and is aberrant in diseases such as cancer. Gene targeting experiments performed in our laboratory revealed that the mouse atonal homolog 1 (Math1) is essential for the formation of most intestinal secretory lineages and suggested an early fate decision between the absorptive and secretory lineages is mediated by Math1. I plan to determine the effects of Math1 loss in the adult intestine, as well as how the secretory lineage defects arise. I hypothesize that (1) Math1 is expressed in a single precursor that is competent to produce all secretory but not absorptive lineages; (2) normal secretory function is necessary for development and proliferative homeostasis of the intestine. I will address these aims by determining Math1 's role in the generation and proliferation of the epithelium of the postnatal intestine, using the Cre/loxP recombination system to specifically delete Math1 in the intestine. I also propose to fate-map Math1 expressing cells to define the ontogenic hierarchy of epithelial cells in normal and Math1-null intestine. These experiments will allow us to elucidate molecular steps required for genesis of the secretory lineages of the intestine, and provide insight into the regulation of development and proliferation in the intestinal mucosa.